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Natural History and Factors Associated with Overall Survival in Stage IV ALK-Rearranged Non-Small Cell Lung Cancer.

ABSTRACT: INTRODUCTION:Clinical variables describing the natural history and longitudinal therapy outcomes of stage IV anaplastic lymphoma kinase gene rearrangement positive (ALK-positive) NSCLC and their relationship with long-term overall survival (OS) have not previously been described in detail. METHODS:Patients with stage IV NSCLC treated with an ALK inhibitor at the University of Colorado Cancer Center from 2009 through November 2017 were identified retrospectively. OS curves were constructed by using Kaplan-Meier methods. Multivariate Cox proportional hazard analysis was used to determine the relationship of variables with OS. RESULTS:Of the 110 patients with ALK-positive NSCLC who were identified, 105 received crizotinib as their initial ALK inhibitor. With a median follow-up time of 47 months, the median OS time from diagnosis of stage IV disease was 81 months (6.8 years). Brain metastases at diagnosis of stage IV disease (hazard ratio = 1.01, p = 0.971) and year of stage IV presentation (p = 0.887) did not influence OS. More organs with tumor at diagnosis of stage IV disease was associated with worse OS (HR = 1.49 for each additional organ with disease, including the CNS [p = 0.002]). Each additional month of pemetrexed-based therapy was associated with a 7% relative decrease in risk of death. CONCLUSION:Patients with stage IV ALK-positive NSCLC can have prolonged OS. Brain metastases at diagnosis of stage IV disease does not influence OS. Having more organs involved with tumor at stage IV presentation is associated with worse outcomes. Prolonged benefit from pemetrexed is associated with better outcomes.

SUBMITTER: Pacheco JM

PROVIDER: S-EPMC7310567 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Natural History and Factors Associated with Overall Survival in Stage IV ALK-Rearranged Non-Small Cell Lung Cancer.

Pacheco Jose M JM Gao Dexiang D Smith Derek D Purcell Thomas T Hancock Mark M Bunn Paul P Robin Tyler T Liu Arthur A Karam Sana S Gaspar Laurie L Kavanagh Brian B Rusthoven Chad C Aisner Dara D Doebele Robert R Camidge D Ross DR

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 20181230 4

<h4>Introduction</h4>Clinical variables describing the natural history and longitudinal therapy outcomes of stage IV anaplastic lymphoma kinase gene rearrangement positive (ALK-positive) NSCLC and their relationship with long-term overall survival (OS) have not previously been described in detail.<h4>Methods</h4>Patients with stage IV NSCLC treated with an ALK inhibitor at the University of Colorado Cancer Center from 2009 through November 2017 were identified retrospectively. OS curves were con ...[more]

PMID: 30599201

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Project description:Non-small-cell lung cancer (NSCLC) harboring the anaplastic lymphoma kinase gene (ALK) rearrangement is sensitive to the ALK inhibitor crizotinib, but resistance invariably develops. Ceritinib (LDK378) is a new ALK inhibitor that has shown greater antitumor potency than crizotinib in preclinical studies.In this phase 1 study, we administered oral ceritinib in doses of 50 to 750 mg once daily to patients with advanced cancers harboring genetic alterations in ALK. In an expansion phase of the study, patients received the maximum tolerated dose. Patients were assessed to determine the safety, pharmacokinetic properties, and antitumor activity of ceritinib. Tumor biopsies were performed before ceritinib treatment to identify resistance mutations in ALK in a group of patients with NSCLC who had had disease progression during treatment with crizotinib.A total of 59 patients were enrolled in the dose-escalation phase. The maximum tolerated dose of ceritinib was 750 mg once daily; dose-limiting toxic events included diarrhea, vomiting, dehydration, elevated aminotransferase levels, and hypophosphatemia. This phase was followed by an expansion phase, in which an additional 71 patients were treated, for a total of 130 patients overall. Among 114 patients with NSCLC who received at least 400 mg of ceritinib per day, the overall response rate was 58% (95% confidence interval [CI], 48 to 67). Among 80 patients who had received crizotinib previously, the response rate was 56% (95% CI, 45 to 67). Responses were observed in patients with various resistance mutations in ALK and in patients without detectable mutations. Among patients with NSCLC who received at least 400 mg of ceritinib per day, the median progression-free survival was 7.0 months (95% CI, 5.6 to 9.5).Ceritinib was highly active in patients with advanced, ALK-rearranged NSCLC, including those who had had disease progression during crizotinib treatment, regardless of the presence of resistance mutations in ALK. (Funded by Novartis Pharmaceuticals and others; ClinicalTrials.gov number, NCT01283516.).

Project description:BackgroundSmall cell lung cancer (SCLC) is associated with aggressive biology and limited treatment options, making this disease a historical challenge. The influence of race and socioeconomic status on the survival of stage IV SCLC remains mostly unknown. Our study is designed to investigate the clinical survival outcomes in Black and White patients with stage IV SCLC and study the demographic, socioeconomic, clinical features, and treatment patterns of the disease and their impact on survival in Blacks and Whites.Methods and resultsStage IV SCLC cases from the National Cancer Database (NCDB) diagnosed between 2004 and 2014 were obtained. The follow-up endpoint is defined as death or the date of the last contact. Patients were divided into two groups by white and black. Features including demographic, socioeconomic, clinical, treatments and survival outcomes in Blacks and Whites were collected. Mortality hazard ratios of Blacks and Whites stage IV SCLC patients were analyzed. Survival of stage IV SCLC Black and White patients was also analyzed. Adjusted hazard ratios were analyzed by Cox proportional hazards regression models. Patients' median follow-up time was 8.18 (2.37-15.84) months. Overall survival at 6, 12, 18 and 24 months were 52.4%, 25.7%, 13.2% and 7.9% in Blacks in compared to 51.0%, 23.6%, 11.5% and 6.9% in Whites. White patients had significantly higher socioeconomic status than Black patients. By contrast, Blacks were found associated with younger age at diagnosis, a significantly higher chance of receiving radiation therapy and treatments at an academic/research program. Compared to Whites, Blacks had a 9% decreased risk of death.ConclusionOur study demonstrated that Blacks have significant socioeconomic disadvantages compared to Whites. However, despite these unfavorable factors, survival for Blacks was significantly improved compared to Whites after covariable adjustment. This may be due to Blacks with Stage IV SCLC having a higher chance of receiving radiation therapy and treatments at an academic/research program. Identifying and removing the barriers to obtaining treatments at academic/research programs or improving the management in non-academic centers could improve the overall survival of stage IV SCLC.

Dataset Information

Natural History and Factors Associated with Overall Survival in Stage IV ALK-Rearranged Non-Small Cell Lung Cancer.

Publications

Natural History and Factors Associated with Overall Survival in Stage IV ALK-Rearranged Non-Small Cell Lung Cancer.

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